Androgens, male sex hormones, regulate biological pathways promoting growth and survival of prostate cancer (PCa). This dependence is exploited by Androgen Targeted Therapies (ATT) in the treatment of advanced PCa using a growing list of inhibitors that target the action of androgens. Although targeting the androgen axis has clear therapeutic benefit in advanced PCa patients, its effectiveness is temporary, as prostate tumour cells adapt to survive and become resistant to subsequent treatments. Our Team’s unified hypothesis is that the ultimate failure of ATT results from the activation of predictable adverse physiological and biological pathways in an adaptive response to ATT. This is exemplified by the induction of features of metabolic syndrome, with increases in potent metabolic hormones, including insulin and other hormones, which promote tumour growth and spread. The tumour microenvironment in bone is also altered by ATT in a manner that may facilitate tumour progression. Removal of androgens promotes plasticity in PCa cells, inducing features that are associated with increased ability to migrate/invade and promote resistance to therapies. Our Team’s expertise in PCa and highly relevant combination of skills sets and biological resources will enable us to uncover innovative insights of the adaptive response of PCa to ATT. We have chosen the specific biological pathways to be investigated because we have convincing evidence that (1) they are consistently activated in PCa patients and our corresponding tumour models in response to ATT, (2) they have significant implications in cancer progression and treatment resistance, and (3) we have novel and re-purposed drugs to target these pathways. Our ultimate goal is to capitalise on adaptive pathways activated by inhibition of the androgen axis to identify and strategically develop drugs to be used in combination or in sequence with ATT to improve outcomes in advanced PCa.

In almost half of all men with prostate cancer, the disease will spread to their bones – a devastating and incurable complication. Sometimes the cancer develops in the skeleton many years after first diagnosis. This suggests that the cancer cells can stay "dormant", or sleeping, and undetected in bones for a long time, but can somehow be triggered to "wake up" and grow. The exact reasons why prostate cancer cells spread to bones, and the triggers that cause the cells to wake up, are not known but probably involve changes in their genes as well as signals from neighbouring bone cells or from cells of the immune system. Identifying these signals could lead to new ways of preventing dormant cancer cells from waking, using either new drugs or using existing anti-cancer drugs in better ways. Uniquely, Prof Croucher has brought together world experts from different fields, including bone cancer, genetics and breast cancer, as well as prostate cancer clinicians, in order to solve this critical problem. For the first time, the team has developed a way to identify dormant cells inside bones under experimental conditions. They can now identify where dormant cells reside in bone and can collect the dormant cells to study how their genes change when the cells wake up. Prof Croucher and his colleagues will collect dormant cells and bone tumours from patients to study how cancer genes change in patients receiving treatment for prostate cancer. They will also identify how bone cells and immune cells may control dormant cells, and whether drugs that affect the bones and immune system may stop dormant cells from waking up. These discoveries aim to revolutionise the treatment and life of prostate cancer patients by findings new ways to prevent cancer growth in bones.

Localised prostate cancer Category

Award 1

Chief Team Leader: A Prof Lisa Butler, PhD, is Head of Prostate Cancer Research Group and an Australian Research Council Future Fellow at School of Medicine, Faculty of Health Sciences, Freemasons Foundation Centre for Men’s Health, University of Adelaide.

Due to advances in detection and management of prostate cancer over the past 20 years, most cases are now potentially curable by surgery or radiotherapy, or amenable to active surveillance. Despite these advances, up to 15% of diagnoses are of high risk localised disease (HRLD), which has a high (30-60%) rate of biochemical recurrence within 10 years, and is increasingly being considered for neoadjuvant or adjuvant therapies. These divergent clinical scenarios have given rise to new dilemmas for disease management, including the inability to (1) distinguish indolent from lethal aggressive forms of prostate cancer, and (2) accurately monitor the efficacy of novel therapeutic agents in individual patients.

Each of these issues emphasise the need for new tailored treatment options and more robust criteria to predict tumour outcomes and to monitor treatment response on an individual patient basis. The collective expertise in prostate tumour biology, lipid metabolism, endocrinology, obesity and clinical management of prostate cancer gives this team unique insights into the complex relationships between lipid composition, androgens and prostate cancer progression. In this Revolutionary Team Award, A Prof Butler’s team will investigate whether altered lipid metabolism in prostate tumour cells provides a hitherto unexplored source of robust prognostic biomarkers for patient outcome and responsiveness to novel therapies that are increasingly being used in neoadjuvant and adjuvant clinical settings. A revolutionary outcome of this program will be the development of non-invasive approaches to detect specific lipid-based profiles in exosomes from the blood and in situ via PET-based molecular imaging to subclassify tumours and monitor clinical responses throughout patient management. Importantly, these findings will be validated in a clinical trial setting for rapid implementation in clinical practice.

Project Grant Category

The SPARK multicentre clinical trial will measure cancer targeting accuracy and patient outcomes in 48 prostate cancer patients. Patients will be treated with a novel cost effective real-time targeting radiotherapy technology developed and pioneered in Australia. The SPARK technology enables prostate cancer patients to be treated in 5 sessions rather than 40 sessions with comparable outcomes. The technology has potential for worldwide benefit for many other cancers e.g. lung, pancreas and liver.

Prostate cancer (PC) is the commonest cancer in Australia and diagnosis usually requires a biopsy called a TRUS, which can be very painful. Many doctors use local anaesthetic but some doctors use sedation instead. This requires an anaesthetist and is costly. The “green whistle” (Penthrox) used in ambulances is safe and effective during TRUS. This trial will test whether Penthrox plus local anaesthetic improves outcomes for men having TRUS compared to local anaesthetic alone.

Young Investigator Category

Prostate cancer is the most common cancer in men. As long as the tumour remains localised within the prostate tissue, the patient has a good prognosis. Unfortunately, many of these men will have their tumours spread and progress to terminal stage disease. This research study will investigate a protein involved in the spread and therapy resistance of prostate cancer. The results obtained from this project will reveal a new biomarker and therapeutic target to inhibit aggressive forms of prostate cancer.